US 2007/0191283 A1 · Method of stimulating the motility of the gastrointestinal system using growth hormone secretagogues

A method of treating opioid induced constipation in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a growth hormone secretagogue compound or a pharmaceutically acceptable salt, hydrate or solvate thereof.

A method of stimulating the motility of the gastrointestinal system in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a growth hormone secretagogue compound, wherein the growth hormone secretagogue compound is represented by the structural Formula I

wherein:
R1 is hydrogen, or C1-6-alkyl optionally substituted with one or more aryl or hetaryl;
a and d are independently 0, 1, 2 or 3;
b and c are independently 0, 1, 2, 3, 4 or 5, provided that b+c is 3, 4 or 5;
D is R2—NH—(CR3R4)e—(CH2)f-M-(CHR5)g—(CH2)h—
wherein:
R2, R3, R4 and R5 are independently hydrogen or C1-6 alkyl optionally substituted with one or more halogen, amino, hydroxyl, aryl or hetaryl;
or
R2 and R3 or R2 and R4 or R3 and R4 can optionally form —(CH2)i—U—(CH2)j—, wherein i and j are independently 1 or 2 and U is —O—, —S— or a valence bond;
h and f are independently 0, 1, 2, or 3;
g and e are independently 0 or 1;
M is a valence bond, —CR6═CR7—, arylene, hetarylene, —O— or —S—;
R6 and R7 are independently hydrogen, or C1-6-alkyl optionally substituted with one or more aryl or hetaryl;
G is —O—(CH2)k—R8,
J is —O—(CH2)l—R13,
wherein:
R8, R9, R10, R11, R12, R13, R14, R15, R16 and R17 independently are hydrogen, halogen, aryl, hetaryl, C1-6-alkyl or C1-6-alkoxy;
k and l are independently 0, 1 or 2;
E is —CONR18R19, —COOR19, —(CH2)m—NR18SO2R20, —(CH2)m—NR18—COR20, —(CH2)m—OR19, —(CH2)m—OCOR20, —CH(R18)R19, —(CH2)m—NR18—CS—NR19R21 or —(CH2)m—R18—CO—NR19R21;
or
E is —CONR22NR23R24, wherein R22 is hydrogen, C1-6-alkyl optionally substituted with one or more aryl or hetaryl, or aryl or hetaryl optionally substituted with one or more C1-6-alkyl;
R23 is C1-6-alkyl optionally substituted with one or more aryl or hetaryl, or C1-7-acyl;
and R24 is hydrogen, C1-6-alkyl optionally substituted with one or more aryl or hetaryl;
or aryl or hetaryl optionally substituted with one or more C1-6-alkyl;
or
R22 and R23 together with the nitrogen atoms to which they are attached can form a heterocyclic system optionally substituted with one or more C1-6-alkyl, halogen, amino, hydroxyl, aryl or hetaryl;
or
R22 and R24 together with the nitrogen atoms to which they are attached can form a heterocyclic system optionally substituted with one or more C1-6-alkyl, halogen, amino, hydroxyl, aryl or hetaryl;
or
R23 and R24 together with the nitrogen atom to which they are attached can form a heterocyclic system optionally substituted with one or more C1-6-alkyl, halogen, amino, hydroxyl, aryl or hetaryl;
wherein m is 0, 1, 2 or 3,
R18, R19 and R21 independently are hydrogen or C1-6-alkyl optionally substituted with halogen, —N(R25)R26, wherein R25 and R26 are independently hydrogen or C1-6 alkyl;
hydroxyl, C1-6-alkoxy, C1-6-alkoxycarbonyl, C1-6-alkylcarbonyloxy or aryl;
or R19 is
wherein
Q is —CH< or —N<,
K and L are independently —CH2—, —CO—, —O—, —S—, —NR27— or a valence bond, where R27 is hydrogen or C1-6 alkyl;
n and o are independently 0, 1, 2, 3 or 4;
R20 is C1-6 alkyl, aryl or hetaryl;
or a pharmaceutically acceptable salt thereof;
with the proviso that if M is a valence bond then E is —CONR22NR23R24.

38 more elements

A method of stimulating the motility of the gastrointestinal system in a subject in need thereof comprising administering to said subject a therapeutically effective amount of growth hormone secretagogue compound, wherein the growth hormone secretagogue compound is represented by the structural Formula IV

wherein
R1 is hydrogen or C1-6-alkyl;
R2 is hydrogen or C1-6-alkyl;
L is
wherein
R4 is hydrogen or C1-6 alkyl;
p is 0 or 1;
q, s, t, u are independently 0, 1, 2, 3, or 4;
r is 1;
the sum q+r+s+t+u is 0, 1, 2, 3, or 4;
R9, R10, R11, and R12 are independently hydrogen or C1-6 alkyl;
Q is >N—R13 or
wherein:
o is 0, 1 or 2;
T is —N(R15)(R16) or hydroxyl;
R13, R15, and R16 are independently hydrogen or C1-6 alkyl;
R14 is hydrogen, aryl or hetaryl;
Or L is
wherein
p is 0 or 1;
q, s, t, u are independently 0, 1, 2, 3, or 4;
r is 0 or 1;
the sum q+r+s+t+u is 0, 1, 2, 3, or 4;
R9, R10, R11, and R12 are independently hydrogen or C1-6 alkyl;
Q is >N—R13 or
wherein
o is 0, 1, or 2;
T is —N(R15)(R16) or hydroxyl;
R13, R15, and R16 are independently from each other hydrogen or C1-6 alkyl;
R14 is hydrogen, aryl, or hetaryl;
G is —O—(CH2)—R17,
wherein:
R17, R18, R19, R20 and R21 independently are hydrogen, halogen, aryl, hetaryl, C1-6-alkyl or C1-6-alkoxy;
K is 0, 1 or 2;
J is —O—(CH2)l—R22,
wherein:
R22, R23, R24, R25 and R26 independently are hydrogen, halogen, aryl, hetaryl, C1-6-alkyl or C1-6-alkoxy;
l is 0, 1 or 2;
a is 0, 1, or 2;
b is 0, 1, or 2;
c is 0, 1, or 2;
d is 0 or 1;
e is 0, 1, 2, or 3;
f is 0 or 1;
R5 is hydrogen or C1-6-alkyl optionally substituted with one or more hydroxyl, aryl or hetaryl;
R6 and R7 are independently hydrogen or C1-6-alkyl, optionally substituted with one or more halogen, amino, hydroxyl, aryl, or hetaryl;
R8 is hydrogen or C1-6-alkyl, optionally substituted with one or more halogen, amino, hydroxyl, aryl, or hetaryl;
R6 and R7 or R6 and R8 or R7 and R8 can optionally form —(CH2)i—U—(CH2)j—, wherein i and j independently are 1, 2 or 3 and U is —O—, —S—, or a valence bond;
M is arylene, hetarylene, —O—, —S— or —CR27═CR28—;
R27 and R28 are independently hydrogen or C1-6-alkyl, optionally substituted with one or more aryl or hetaryl;
or a pharmaceutically acceptable salt thereof.

48 more elements

A method of treating diabetes related gastroparesis in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a growth hormone secretagogue compound, wherein the growth hormone secretagogue compound is represented by the structural Formula I

wherein:
R1 is hydrogen, or C1-6-alkyl optionally substituted with one or more aryl or hetaryl;
a and d are independently 0, 1, 2 or 3;
b and c are independently 0, 1, 2, 3, 4 or 5, provided that b+c is 3, 4 or 5;
D is R2—NH—(CR3R4)e—(CH2)f-M-(CHR5)g—(CH2)h—
wherein:
R2, R3, R4 and R5 are independently hydrogen or C1-6 alkyl optionally substituted with one or more halogen, amino, hydroxyl, aryl or hetaryl;
or
R2 and R3 or R2 and R4 or R3 and R4 can optionally form —(CH2)i—U—(CH2)j—, wherein i and j are independently 1 or 2 and U is —O—, —S— or a valence bond;
h and f are independently 0, 1, 2, or 3;
g and e are independently 0 or 1;
M is a valence bond, —CR6═CR7—, arylene, hetarylene, —O— or —S—;
R6 and R7 are independently hydrogen, or C1-6-alkyl optionally substituted with one or more aryl or hetaryl;
G is —(CH2)k—R8,
J is —(CH2)l—R13,
wherein:
R8, R9, R10, R11, R12, R13, R14, R15, R16 and R17 independently are hydrogen, halogen, aryl, hetaryl, C1-6-alkyl or C1-6-alkoxy;
k and l are independently 0, 1 or 2;
E is —CONR18R19, —COOR19, —(CH2)m—NR18SO2R20, —(CH2)m—NR18—COR20, —(CH2)m—OR19, —(CH2)m—OCOR20, —CH(R18)R19, —(CH2)m—NR18—CS—NR19R21 or —(CH2)m—NR18—CO—NR19R21;
or
E is —CONR22NR23R24, wherein R22 is hydrogen, C1-6-alkyl optionally substituted with one or more aryl or hetaryl, or aryl or hetaryl optionally substituted with one or more C1-6-alkyl;
R23 is C1-6-alkyl optionally substituted with one or more aryl or hetaryl, or C1-7-acyl;
and R24 is hydrogen, C1-6-alkyl optionally substituted with one or more aryl or hetaryl;
or aryl or hetaryl optionally substituted with one or more C1-6-alkyl;
or
R22 and R23 together with the nitrogen atoms to which they are attached can form a heterocyclic system optionally substituted with one or more C1-6-alkyl, halogen, amino, hydroxyl, aryl or hetaryl;
or
R22 and R24 together with the nitrogen atoms to which they are attached can form a heterocyclic system optionally substituted with one or more C1-6-alkyl, halogen, amino, hydroxyl, aryl or hetaryl;
or
R23 and R24 together with the nitrogen atom to which they are attached can form a heterocyclic system optionally substituted with one or more C1-6-alkyl, halogen, amino, hydroxyl, aryl or hetaryl;
wherein m is 0, 1, 2 or 3,
R18, R19 and R21 independently are hydrogen or C1-6-alkyl optionally substituted with halogen, —N(R25)R26, wherein R25 and R26 are independently hydrogen or C1-6 alkyl;
hydroxyl, C1-6-alkoxy, C1-6-alkoxycarbonyl, C1-6-alkylcarbonyloxy or aryl;
or R19 is
wherein
Q is —CH< or —N<,
K and L are independently —CH2, —CO—, —O—, —S—, —NR27— or a valence bond, where R27 is hydrogen or C1-6 alkyl;
n and o are independently 0, 1, 2, 3 or 4;
R20 is C1-6 alkyl, aryl or hetaryl;
or a pharmaceutically acceptable salt thereof;
with the proviso that if M is a valence bond then E is —CONR22NR23R24.

38 more elements

A method of treating diabetes related gastroparesis in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a growth hormone secretagogue compound, wherein the growth hormone secretagogue compound is represented by the structural Formula IV

wherein
R1 is hydrogen or C1-6-alkyl;
R2 is hydrogen or C1-6-alkyl;
L is
wherein
R4 is hydrogen or C1-6 alkyl;
p is 0 or 1;
q, s, t, u are independently 0, 1, 2, 3, or 4;
r is 1;
the sum q+r+s+t+u is 0, 1, 2, 3, or 4;
R9, R10, R11, and R12 are independently hydrogen or C1-6 alkyl;
Q is >N—R13 or
wherein:
o is 0, 1 or 2;
T is —N(R15)(R16) or hydroxyl;
R13, R15, and R16 are independently hydrogen or C1-6 alkyl;
R14 is hydrogen, aryl or hetaryl;
Or L is
wherein
p is 0 or 1;
q, s, t, u are independently 0, 1, 2, 3, or 4;
r is 0 or 1;
the sum q+r+s+t+u is 0, 1, 2, 3, or 4;
R9, R10, R11, and R12 are independently hydrogen or C1-6 alkyl;
Q is >N—R13 or
wherein
o is 0, 1, or 2;
T is —N(R15)(R16) or hydroxyl;
R13, R15, and R16 are independently from each other hydrogen or C1-6 alkyl;
R14 is hydrogen, aryl, or hetaryl;
G is —O—(CH2)—R17,
wherein:
R17, R18, R19, R20 and R21 independently are hydrogen, halogen, aryl, hetaryl, C1-6-alkyl or C1-6-alkoxy;
K is 0, 1 or 2;
J is —O—(CH2)1—R22,
wherein:
R22, R23, R24, R25 and R26 independently are hydrogen, halogen, aryl, hetaryl, C1-6-alkyl or C1-6-alkoxy;
l is 0, 1 or 2;
a is 0, 1, or 2;
b is 0, 1, or 2;
c is 0, 1, or 2;
d is 0 or 1;
e is 0, 1, 2, or 3;
f is 0 or 1;
R5 is hydrogen or C1-6-alkyl optionally substituted with one or more hydroxyl, aryl or hetaryl;
R6 and R7 are independently hydrogen or C1-6-alkyl, optionally substituted with one or more halogen, amino, hydroxyl, aryl, or hetaryl;
R8 is hydrogen or C1-6-alkyl, optionally substituted with one or more halogen, amino, hydroxyl, aryl, or hetaryl;
R6 and R7 or R6 and R8 or R7 and R8 can optionally form —(CH2)i—U—(CH2)j—, wherein i and j independently are 1, 2 or 3 and U is —O—, —S—, or a valence bond;
M is arylene, hetarylene, —O—, —S— or —CR27═CR28—;
R27 and R28 are independently hydrogen or C1-6-alkyl, optionally substituted with one or more aryl or hetaryl;
or a pharmaceutically acceptable salt thereof.

48 more elements

A method of treating gastroesophageal reflux disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a growth hormone secretagogues compound, wherein the growth hormone secretagogue compound is represented by the structural Formula I,

wherein:
R1 is hydrogen, or C1-6-alkyl optionally substituted with one or more aryl or hetaryl;
a and d are independently 0, 1, 2 or 3;
b and c are independently 0, 1, 2, 3, 4 or 5, provided that b+c is 3, 4 or 5;
D is R2—NH—(CR3R4)e—(CH2)f-M-(CHR5)g—(CH2)h—
wherein:
R2, R3, R4 and R5 are independently hydrogen or C1-6 alkyl optionally substituted with one or more halogen, amino, hydroxyl, aryl or hetaryl;
or
R2 and R3 or R2 and R4 or R3 and R4 can optionally form —(CH2)i—U—(CH2)j—, wherein i and j are independently 1 or 2 and U is —O—, —S— or a valence bond;
h and f are independently 0, 1, 2, or 3;
g and e are independently 0 or 1;
M is a valence bond, —CR6═CR7—, arylene, hetarylene, —O— or —S—;
R6 and R7 are independently hydrogen, or C1-6-alkyl optionally substituted with one or more aryl or hetaryl;
G is —O—(CH2)k—R8,
J is —O—(CH2)l—R13,
wherein:
R8, R9, R10, R11, R12, R13, R14, R15, R16 and R17 independently are hydrogen, halogen, aryl, hetaryl, C1-6-alkyl or C1-6-alkoxy;
k and l are independently 0, 1 or 2;
E is —CONR18R19, —COOR19, —(CH2)m—NR18SO2R20, —(CH2)m—NR18—COR20, —(CH2)m—OR19, —(CH2)m—OCOR20, —CH(R18)R19, —(CH2)m—NR18—CS—NR19R21 or —(CH2)m—NR18—CO—NR19R21;
or
E is —CONR22NR23R24, wherein R22 is hydrogen, C1-6-alkyl optionally substituted with one or more aryl or hetaryl, or aryl or hetaryl optionally substituted with one or more C1-6-alkyl;
R23 is C1-6-alkyl optionally substituted with one or more aryl or hetaryl, or C1-7-acyl;
and R24 is hydrogen, C1-6-alkyl optionally substituted with one or more aryl or hetaryl;
or aryl or hetaryl optionally substituted with one or more C1-6-alkyl;
or
R22 and R23 together with the nitrogen atoms to which they are attached can form a heterocyclic system optionally substituted with one or more C1-6-alkyl, halogen, amino, hydroxyl, aryl or hetaryl;
or
R22 and R24 together with the nitrogen atoms to which they are attached can form a heterocyclic system optionally substituted with one or more C1-6-alkyl, halogen, amino, hydroxyl, aryl or hetaryl;
or
R23 and R24 together with the nitrogen atom to which they are attached can form a heterocyclic system optionally substituted with one or more C1-6-alkyl, halogen, amino, hydroxyl, aryl or hetaryl;
wherein m is 0, 1, 2 or 3,
R18, R19 and R21 independently are hydrogen or C1-6-alkyl optionally substituted with halogen, —N(R25)R26, wherein R25 and R26 are independently hydrogen or C1-6 alkyl;
hydroxyl, C1-6-alkoxy, C1-6-alkoxycarbonyl, C1-6-alkylcarbonyloxy or aryl;
or R19 is
wherein
Q is —CH< or —N<,
K and L are independently —CH2—, —CO—, —O—, —S—, —NR27— or a valence bond, where R27 is hydrogen or C1-6 alkyl;
n and o are independently 0, 1, 2, 3 or 4;
R20 is C1-6 alkyl, aryl or hetaryl;
or a pharmaceutically acceptable salt thereof;
with the proviso that if M is a valence bond then E is —CONR22NR23R24.

38 more elements

A method of treating gastroesophageal reflux disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a growth hormone secretagogues compound, wherein the growth hormone secretagogue compound is represented by the structural Formula IV

wherein
R1 is hydrogen or C1-6-alkyl;
R2 is hydrogen or C1-6-alkyl;
L is
wherein
R4 is hydrogen or C1-6 alkyl;
p is 0 or 1;
q, s, t, u are independently 0, 1, 2, 3, or 4;
r is 1;
the sum q+r+s+t+u is 0, 1, 2, 3, or 4;
R9, R10, R11, and R12 are independently hydrogen or C1-6 alkyl;
Q is >N—R13 or
wherein:
o is 0, 1 or 2;
T is —N(R15)(R16) or hydroxyl;
R13, R15, and R16 are independently hydrogen or C1-6 alkyl;
R14 is hydrogen, aryl or hetaryl;
Or L is
wherein
p is 0 or 1;
q, s, t, u are independently 0, 1, 2, 3, or 4;
r is 0 or 1;
the sum q+r+s+t+u is 0, 1, 2, 3, or 4;
R9, R10, R11, and R12 are independently hydrogen or C1-6 alkyl;
Q is >N—R13 or
wherein
o is 0, 1, or 2;
T is —N(R15)(R16) or hydroxyl;
R13, R15, and R16 are independently from each other hydrogen or C1-6 alkyl;
R14 is hydrogen, aryl, or hetaryl;
G is —O—(CH2)—R17,
wherein:
R17, R18, R19, R20 and R21 independently are hydrogen, halogen, aryl, hetaryl, C1-6-alkyl or C1-6-alkoxy;
K is 0, 1 or 2;
J is —O—(CH2)l—R22,
wherein:
R22, R23, R24, R25 and R26 independently are hydrogen, halogen, aryl, hetaryl, C1-6-alkyl or C1-6-alkoxy;
l is 0, 1 or 2;
a is 0, 1, or 2;
b is 0, 1, or 2;
c is 0, 1, or 2;
d is 0 or 1;
e is 0, 1, 2, or 3;
f is 0 or 1;
R5 is hydrogen or C1-6-alkyl optionally substituted with one or more hydroxyl, aryl or hetaryl;
R6 and R7 are independently hydrogen or C1-6-alkyl, optionally substituted with one or more halogen, amino, hydroxyl, aryl, or hetaryl;
R8 is hydrogen or C1-6-alkyl, optionally substituted with one or more halogen, amino, hydroxyl, aryl, or hetaryl;
R6 and R7 or R6 and R8 or R7 and R8 can optionally form —(CH2)i—U—(CH2)j—, wherein i and j independently are 1, 2 or 3 and U is —O—, —S—, or a valence bond;
M is arylene, hetarylene, —O—, —S— or —CR27═CR28—;
R27 and R28 are independently hydrogen or C1-6-alkyl, optionally substituted with one or more aryl or hetaryl;
or a pharmaceutically acceptable salt thereof.

48 more elements

The method of treating irritable bowel syndrome in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a growth hormone secretagogues compound, wherein the growth hormone secretagogue compound is represented by the structural Formula I:

wherein:
R1 is hydrogen, or C1-6-alkyl optionally substituted with one or more aryl or hetaryl;
a and d are independently 0, 1, 2 or 3;
b and c are independently 0, 1, 2, 3, 4 or 5, provided that b+c is 3, 4 or 5;
D is R2—NH—(CR3R4)e—(CH2)f-M-(CHR5)g—(CH2)h—
wherein:
R2, R3, R4 and R5 are independently hydrogen or C1-6 alkyl optionally substituted with one or more halogen, amino, hydroxyl, aryl or hetaryl;
or
R2 and R3 or R2 and R4 or R3 and R4 can optionally form —(CH2)i—U—(CH2)j—, wherein i and j are independently 1 or 2 and U is —O—, —S— or a valence bond;
h and f are independently 0, 1, 2, or 3;
g and e are independently 0 or 1;
M is a valence bond, —CR6═CR7—, arylene, hetarylene, —O— or —S—;
R6 and R7 are independently hydrogen, or C1-6-alkyl optionally substituted with one or more aryl or hetaryl;
G is —O—(CH2)k—R8,
J is —O—(CH2)l—R13,
wherein:
R8, R9, R10, R11, R12, R13, R14, R15, R16 and R17 independently are hydrogen, halogen, aryl, hetaryl, C1-6-alkyl or C1-6-alkoxy;
k and l are independently 0, 1 or 2;
E is —CONR18R19, —COOR19, —(CH2)m—NR18SO2R20, —(CH2)m—NR18—COR20, —(CH2)m—OR19, —(CH2)m—OCOR20, —CH(R18)R19, —(CH2)m—NR18—CS—NR19R21 or —(CH2)m—NR18—CO—NR19R21;
or
E is —CONR22NR23R24, wherein R22 is hydrogen, C1-6-alkyl optionally substituted with one or more aryl or hetaryl, or aryl or hetaryl optionally substituted with one or more C1-6-alkyl;
R23 is C1-6-alkyl optionally substituted with one or more aryl or hetaryl, or C1-7-acyl;
and R24 is hydrogen, C1-6-alkyl optionally substituted with one or more aryl or hetaryl;
or aryl or hetaryl optionally substituted with one or more C1-6-alkyl;
or
R22 and R23 together with the nitrogen atoms to which they are attached can form a heterocyclic system optionally substituted with one or more C1-6-alkyl, halogen, amino, hydroxyl, aryl or hetaryl;
or
R22 and R24 together with the nitrogen atoms to which they are attached can form a heterocyclic system optionally substituted with one or more C1-6-alkyl, halogen, amino, hydroxyl, aryl or hetaryl;
or
R23 and R24 together with the nitrogen atom to which they are attached can form a heterocyclic system optionally substituted with one or more C1-6-alkyl, halogen, amino, hydroxyl, aryl or hetaryl;
wherein m is 0, 1, 2 or 3,
R18, R19 and R21 independently are hydrogen or C1-6-alkyl optionally substituted with halogen, —N(R25)R26, wherein R25 and R26 are independently hydrogen or C1-6 alkyl;
hydroxyl, C1-6-alkoxy, C1-6-alkoxycarbonyl, C1-6-alkylcarbonyloxy or aryl;
or R19 is
wherein
Q is —CH< or —N<,
K and L are independently —CH2—, —CO—, —O—, —S—, —NR27— or a valence bond, where R27 is hydrogen or C1-6 alkyl;
n and o are independently 0, 1, 2, 3 or 4;
R20 is C1-6 alkyl, aryl or hetaryl;
or a pharmaceutically acceptable salt thereof;
with the proviso that if M is a valence bond then E is —CONR22NR23R24.

38 more elements

A method of treating irritable bowel syndrome in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a growth hormone secretagogues compound, wherein the growth hormone secretagogue compound is represented by the structural Formula IV:

wherein
R1 is hydrogen or C1-6-alkyl;
R2 is hydrogen or C1-6-alkyl;
L is
wherein
R4 is hydrogen or C1-6 alkyl;
p is 0 or 1;
q, s, t, u are independently 0, 1, 2, 3, or 4;
r is 1;
the sum q+r+s+t+u is 0, 1, 2, 3, or 4;
R9, R10, R11, and R12 are independently hydrogen or C1-6 alkyl;
Q is >N—R13 or
wherein:
o is 0, 1 or 2;
T is —N(R15)(R16) or hydroxyl;
R13, R15, and R16 are independently hydrogen or C1-6 alkyl;
R14 is hydrogen, aryl or hetaryl;
Or L is
wherein
p is 0 or 1;
q, s, t, u are independently 0, 1, 2, 3, or 4;
r is 0 or 1;
the sum q+r+s+t+u is 0, 1, 2, 3, or 4;
R9, R10, R11, and R12 are independently hydrogen or C1-6 alkyl;
Q is >N—R13 or
wherein
o is 0, 1, or 2;
T is —N(R15)(R16) or hydroxyl;
R13, R15, and R16 are independently from each other hydrogen or C1-6 alkyl;
R14 is hydrogen, aryl, or hetaryl;
G is —O—(CH2)—R17,
wherein:
R17, R18, R19, R20 and R21 independently are hydrogen, halogen, aryl, hetaryl, C1-6-alkyl or C1-6-alkoxy;
K is 0, 1 or 2;
J is —O—(CH2)n—R22,
wherein:
R22, R23, R24, R25 and R26 independently are hydrogen, halogen, aryl, hetaryl, C1-6-alkyl or C1-6-alkoxy;
l is 0, 1 or 2;
a is 0, 1, or 2;
b is 0, 1, or 2;
c is 0, 1, or 2;
d is 0 or 1;
e is 0, 1, 2, or 3;
f is 0 or 1;
R5 is hydrogen or C1-6-alkyl optionally substituted with one or more hydroxyl, aryl or hetaryl;
R6 and R7 are independently hydrogen or C1-6-alkyl, optionally substituted with one or more halogen, amino, hydroxyl, aryl, or hetaryl;
R8 is hydrogen or C1-6-alkyl, optionally substituted with one or more halogen, amino, hydroxyl, aryl, or hetaryl;
R6 and R7 or R6 and R8 or R7 and R8 can optionally form —(CH2)i—U—(CH2)j—, wherein i and j independently are 1, 2 or 3 and U is —O—, —S—, or a valence bond;
M is arylene, hetarylene, —O—, —S— or —CR27═CR28—;
R27 and R28 are independently hydrogen or C1-6-alkyl, optionally substituted with one or more aryl or hetaryl;
or a pharmaceutically acceptable salt thereof.

48 more elements

A method of treating constipation in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a growth hormone secretagogues compound, wherein the growth hormone secretagogue compound is represented by the structural Formula I

wherein:
R1 is hydrogen, or C1-6-alkyl optionally substituted with one or more aryl or hetaryl;
a and d are independently 0, 1, 2 or 3;
b and c are independently 0, 1, 2, 3, 4 or 5, provided that b+c is 3, 4 or 5;
D is R2—NH—(CR3R4)e—(CH2)f-M-(CHR5)g—(CH2)h—
wherein:
R2, R3, R4 and R5 are independently hydrogen or C1-6 alkyl optionally substituted with one or more halogen, amino, hydroxyl, aryl or hetaryl;
or
R2 and R3 or R2 and R4 or R3 and R4 can optionally form —(CH2)i—U—(CH2)j—, wherein i and j are independently 1 or 2 and U is —O—, —S— or a valence bond;
h and f are independently 0, 1, 2, or 3;
g and e are independently 0 or 1;
M is a valence bond, —CR6CR7—, arylene, hetarylene, —O— or —S—;
R6 and R7 are independently hydrogen, or C1-6-alkyl optionally substituted with one or more aryl or hetaryl;
G is —O—(CH2)k—R8,
J is —O—(CH2)l—R13,
wherein:
R8, R9, R10, R11, R12, R13, R14, R15, R16 and R17 independently are hydrogen, halogen, aryl, hetaryl, C1-6-alkyl or C1-6-alkoxy;
k and l are independently 0, 1 or 2;
E is —CONR18R19, —COOR19, —(CH2)m—NR18SO2R20, —(CH2)m—NR18—COR20, —(CH2)m—OR19, —(CH2)m—OCOR20, —CH(R18)R19, —(CH2)m—NR18—CS—NR19R21 or —(CH2)m—NR18—CO—NR19R21;
or
E is —CONR22NR23R24, wherein R22 is hydrogen, C1-6-alkyl optionally substituted with one or more aryl or hetaryl, or aryl or hetaryl optionally substituted with one or more C1-6-alkyl;
R23 is C1-6-alkyl optionally substituted with one or more aryl or hetaryl, or C1-7-acyl;
and R24 is hydrogen, C1-6-alkyl optionally substituted with one or more aryl or hetaryl;
or aryl or hetaryl optionally substituted with one or more C1-6-alkyl;
or
R22 and R23 together with the nitrogen atoms to which they are attached can form a heterocyclic system optionally substituted with one or more C1-6-alkyl, halogen, amino, hydroxyl, aryl or hetaryl;
or
R22 and R24 together with the nitrogen atoms to which they are attached can form a heterocyclic system optionally substituted with one or more C1-6-alkyl, halogen, amino, hydroxyl, aryl or hetaryl;
or
R23 and R24 together with the nitrogen atom to which they are attached can form a heterocyclic system optionally substituted with one or more C1-6-alkyl, halogen, amino, hydroxyl, aryl or hetaryl;
wherein m is 0, 1, 2 or 3,
R18, R19 and R21 independently are hydrogen or C1-6-alkyl optionally substituted with halogen, —N(R25)R26, wherein R25 and R26 are independently hydrogen or C1-6 alkyl;
hydroxyl, C1-6-alkoxy, C1-6-alkoxycarbonyl, C1-6-alkylcarbonyloxy or aryl;
or R19 is
wherein
Q is —CH< or —N<,
K and L are independently —CH2—, —CO—, —O—, —S—, —NR27— or a valence bond, where R27 is hydrogen or C1-6 alkyl;
n and o are independently 0, 1, 2, 3 or 4;
R20 is C1-6 alkyl, aryl or hetaryl;
or a pharmaceutically acceptable salt thereof;
with the proviso that if M is a valence bond then E is —CONR22NR23R24.

38 more elements

A method of treating constipation in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a growth hormone secretagogues compound, wherein the growth hormone secretagogue compound is represented by the structural Formula IV

wherein
R1 is hydrogen or C1-6-alkyl;
R2 is hydrogen or C1-6-alkyl;
L is
wherein
R4 is hydrogen or C1-6 alkyl;
p is 0 or 1;
q, s, t, u are independently 0, 1, 2, 3, or 4;
r is 1;
the sum q+r+s+t+u is 0, 1, 2, 3, or 4;
R9, R10, R11, and R12 are independently hydrogen or C1-6 alkyl;
Q is >N—R13 or
wherein:
o is 0, 1 or 2;
T is —N(R15)(R16) or hydroxyl;
R13, R15, and R16 are independently hydrogen or C1-6 alkyl;
R14 is hydrogen, aryl or hetaryl;
Or L is
wherein
p is 0 or 1;
q, s, t, u are independently 0, 1, 2, 3, or 4;
r is 0 or 1;
the sum q+r+s+t+u is 0, 1, 2, 3, or 4;
R9, R10, R11, and R12 are independently hydrogen or C1-6 alkyl;
Q is >N—R13 or
wherein
o is 0, 1, or 2;
T is —N(R15)(R16) or hydroxyl;
R13, R15, and R16 are independently from each other hydrogen or C1-6 alkyl;
R14 is hydrogen, aryl, or hetaryl;
G is —O—(CH2)—R17,
wherein:
R17, R18, R19, R20 and R21 independently are hydrogen, halogen, aryl, hetaryl, C1-6-alkyl or C1-6-alkoxy;
K is 0, 1 or 2;
J is —O—(CH2)l—R22,
wherein:
R22, R23, R24, R25 and R26 independently are hydrogen, halogen, aryl, hetaryl, C1-6-alkyl or C1-6-alkoxy;
l is 0, 1 or 2;
a is 0, 1, or 2;
b is 0, 1, or 2;
c is 0, 1, or 2;
d is 0 or 1;
e is 0, 1, 2, or 3;
f is 0 or 1;
R5 is hydrogen or C1-6-alkyl optionally substituted with one or more hydroxyl, aryl or hetaryl;
R6 and R7 are independently hydrogen or C1-6-alkyl, optionally substituted with one or more halogen, amino, hydroxyl, aryl, or hetaryl;
R8 is hydrogen or C1-6-alkyl, optionally substituted with one or more halogen, amino, hydroxyl, aryl, or hetaryl;
R6 and R7 or R6 and R8 or R7 and R8 can optionally form —(CH2)i—U—(CH2)j—, wherein i and j independently are 1, 2 or 3 and U is —O—, —S—, or a valence bond;
M is arylene, hetarylene, —O—, —S— or —CR27═CR28—;
R27 and R28 are independently hydrogen or C1-6-alkyl, optionally substituted with one or more aryl or hetaryl;
or a pharmaceutically acceptable salt thereof.

48 more elements

A method of treating post-operative ileus in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a growth hormone secretagogues compound, wherein the growth hormone secretagogue compound is represented by the structural Formula I:

wherein:
R1 is hydrogen, or C1-6-alkyl optionally substituted with one or more aryl or hetaryl;
a and d are independently 0, 1, 2 or 3;
b and c are independently 0, 1, 2, 3, 4 or 5, provided that b+c is 3, 4 or 5;
D is R2—NH—(CR3R4)e—(CH2)f-M-(CHR5)g—(CH2)h—
wherein:
R2, R3, R4 and R5 are independently hydrogen or C1-6 alkyl optionally substituted with one or more halogen, amino, hydroxyl, aryl or hetaryl;
or
R2 and R3 or R2 and R4 or R3 and R4 can optionally form —(CH2)i—U—(CH2)j—, wherein i and j are independently 1 or 2 and U is —O—, —S— or a valence bond;
h and f are independently 0, 1, 2, or 3;
g and e are independently 0 or 1;
M is a valence bond, —CR6═CR7—, arylene, hetarylene, —O— or —S—;
R6 and R7 are independently hydrogen, or C1-6-alkyl optionally substituted with one or more aryl or hetaryl;
G is —O—(CH2)k—R8,
J is —O—(CH2)lR13,
wherein:
R8, R9, R10, R11, R12, R13, R14, R15, R16 and R17 independently are hydrogen, halogen, aryl, hetaryl, C1-6-alkyl or C1-6-alkoxy;
k and l are independently 0, 1 or 2;
E is —CONR18R19, —COOR19, —(CH2)m—NR18SO2R20, —(CH2)m—NR18—COR20, —(CH2)m—OR19, —(CH2)m—OCOR20, —CH(R18)R19, —(CH2)m—NR18—CS—NR19R21 or —(CH2)m—NR18—CO—NR19R21;
or
E is —CONR22NR23R24, wherein R22 is hydrogen, C1-6-alkyl optionally substituted with one or more aryl or hetaryl, or aryl or hetaryl optionally substituted with one or more C1-6-alkyl;
R23 is C1-6-alkyl optionally substituted with one or more aryl or hetaryl, or C1-7-acyl;
and R24 is hydrogen, C1-6-alkyl optionally substituted with one or more aryl or hetaryl;
or aryl or hetaryl optionally substituted with one or more C1-6-alkyl;
or
R22 and R23 together with the nitrogen atoms to which they are attached can form a heterocyclic system optionally substituted with one or more C1-6-alkyl, halogen, amino, hydroxyl, aryl or hetaryl;
or
R22 and R24 together with the nitrogen atoms to which they are attached can form a heterocyclic system optionally substituted with one or more C1-6-alkyl, halogen, amino, hydroxyl, aryl or hetaryl;
or
R23 and R24 together with the nitrogen atom to which they are attached can form a heterocyclic system optionally substituted with one or more C1-6 alkyl, halogen, amino, hydroxyl, aryl or hetaryl;
wherein m is 0, 1, 2 or 3,
R18, R19 and R21 independently are hydrogen or C1-6-alkyl optionally substituted with halogen, —N(R25)R26, wherein R25 and R26 are independently hydrogen or C1-6 alkyl;
hydroxyl, C1-6-alkoxy, C1-6-alkoxycarbonyl, C1-6-alkylcarbonyloxy or aryl;
or R19 is
wherein
Q is —CH< or —N<,
K and L are independently —CH2—, —CO—, —O—, —S—, —NR27— or a valence bond, where R27 is hydrogen or C1-6 alkyl;
n and o are independently 0, 1, 2, 3 or 4;
R20 is C1-6 alkyl, aryl or hetaryl;
or a pharmaceutically acceptable salt thereof;
with the proviso that if M is a valence bond then E is —CONR22NR23R24.

38 more elements

A method of treating post-operative ileus in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a growth hormone secretagogues compound, wherein the growth hormone secretagogue compound is represented by the structural Formula IV

wherein
R1 is hydrogen or C1-6-alkyl;
R2 is hydrogen or C1-6-alkyl;
L is
wherein
R4 is hydrogen or C1-6 alkyl;
p is 0 or 1;
q, s, t, u are independently 0, 1, 2, 3, or 4;
r is 1;
the sum q+r+s+t+u is 0, 1, 2, 3, or 4;
R9, R10, R11, and R12 are independently hydrogen or C1-6 alkyl;
Q is >N—R13 or
wherein:
o is 0, 1 or 2;
T is —N(R15)(R16) or hydroxyl;
R13, R15, and R16 are independently hydrogen or C1-6 alkyl;
R14 is hydrogen, aryl or hetaryl;
Or L is
wherein
p is 0 or 1;
q, s, t, u are independently 0, 1, 2, 3, or 4;
r is 0 or 1;
the sum q+r+s+t+u is 0, 1, 2, 3, or 4;
R9, R10, R11, and R12 are independently hydrogen or C1-6 alkyl;
Q is >N—R13 or
wherein
o is 0, 1, or 2;
T is —N(R15)(R16) or hydroxyl;
R13, R15, and R16 are independently from each other hydrogen or C1-6 alkyl;
R14 is hydrogen, aryl, or hetaryl;
G is —O—(CH2)—R17,
wherein:
R17, R18, R19, R20 and R21 independently are hydrogen, halogen, aryl, hetaryl, C1-6-alkyl or C1-6-alkoxy;
K is 0, 1 or 2;
J is —O—(CH2)l—R22,
wherein:
R22, R23, R24, R25 and R26 independently are hydrogen, halogen, aryl, hetaryl, C1-6-alkyl or C1-6-alkoxy;
l is 0, 1 or 2;
a is 0, 1, or 2;
b is 0, 1, or 2;
c is 0, 1, or 2;
d is 0 or 1;
e is 0, 1, 2, or 3;
f is 0 or 1;
R5 is hydrogen or C1-6-alkyl optionally substituted with one or more hydroxyl, aryl or hetaryl;
R6 and R7 are independently hydrogen or C1-6-alkyl, optionally substituted with one or more halogen, amino, hydroxyl, aryl, or hetaryl;
R8 is hydrogen or C1-6-alkyl, optionally substituted with one or more halogen, amino, hydroxyl, aryl, or hetaryl;
R6 and R7 or R6 and R8 or R7 and R8 can optionally form —(CH2)i—U—(CH2)j—, wherein i and j independently are 1, 2 or 3 and U is —O—, —S—, or a valence bond;
M is arylene, hetarylene, —O—, —S— or —CR27═CR28—;
R27 and R28 are independently hydrogen or C1-6-alkyl, optionally substituted with one or more aryl or hetaryl;
or a pharmaceutically acceptable salt thereof.

48 more elements

Method of stimulating the motility of the gastrointestinal system using growth hormone secretagogues

Life of this patent

Method of stimulating the motility of the gastrointestinal system using growth hormone secretagogues

Life of this patent

Abstract

Claims75